Dartmouth Bioengineers Develop Humanized Yeast

Bioengineers at Dartmouth have genetically engineered yeast to produce humanized therapeutic proteins to address the manufacturing crunch currently confronting the biopharmaceutical industry. Reported in this week's issue of Science, the researchers have re-engineered the yeast P. pastoris to secrete a complex human glycoprotein-a process offering significant advantages over current production methods using mammalian cell lines, according to the researchers.

The study, titled "Production of Complex Human Glycoproteins in Yeast," is one result of a collaboration between researchers at Dartmouth's Thayer School of Engineering and GlycoFi, Inc., a biotech company located in Lebanon, New Hampshire. Founded in the spring of 2000 by Dartmouth engineering professors Tillman Gerngross and Charles Hutchinson, GlycoFi is advancing technology for the production of humanized proteins using fungal-based expression systems.

"For the first time, we have shown that yeast can be used to produce a complex human glycoprotein," says Professor Gerngross. "This technology has the potential to revolutionize the way therapeutic proteins are made-better, cheaper, faster, safer-and offer a level of control over the quality of the end product that has never existed before."

Proteins for pharmaceuticals must be manufactured by living cells. These cells are genetically engineered to produce (or express) proteins that mimic the ones synthesized by humans. These proteins can then be used to treat diseases ranging from cancer and multiple sclerosis to hemophilia and renal disease.

"This technology has the potential to revolutionize the way therapeutic proteins are made."

-Tillman Gerngross

Current production of these therapeutic proteins, however, is limited by capacity due to rapid growth in the discovery of protein-based therapies-to the point that some approved drugs cannot be produced in adequate amounts, and still others are not making it into commercialization due to cost-prohibitive production methods.

"This development is very timely considering the production capacity bottleneck that's facing today's biomanufacturing industry," notes Hutchinson, CEO of GlycoFi and Dean Emeritus of Thayer School.

The Dartmouth researchers genetically engineered the yeast P. pastoris to perform a series of sequential reactions (pathways) that mimic the processing of proteins in humans. After eliminating non-human pathways from the yeast, five genes were inserted causing the yeast to construct a new secretion pathway that synthesizes human-like glycoprotein structures of superior quality.

"The protein structures we are seeing in our yeast are of a purity and uniformity unprecedented in biopharmaceutical manufacturing," said Stefan Wildt, Director of Strain Development at GlycoFi, and one of the authors of the paper. "This makes it possible to harness both the inherent advantages of fungal protein expression systems and the potential to significantly increase pharmaceutical production capacities, therefore ultimately improving patient access to life-saving drug therapies."

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